Introduction

Guide To Beating Hypoglycemia

Most Effective Hypoglycemia Treatments

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Denson G. Fujikawa

In the early 1980s it was recognized that excessive Ca2+ influx, presumably through voltage-gated Ca2+ channels, with a resultant increase in intracellular Ca2+, was associated with neuronal death from cerebral ischemia, hypoglycemia, and status epilepticus (Siejo 1981). Calcium activation of phospholipases, with arachidonic acid accumulation and its oxidation, generating free radicals, was thought to be a potential mechanism by which neuronal damage occurs. In cerebral ischemia and hypoglycemia, energy failure was thought to be the reason for excessive Ca2+ influx, whereas in status epilepticus it was thought that repetitive depolarizations were responsible (Siejo 1981).

Meanwhile, John Olney found that monosodium glutamate, the food additive, when given to immature rats, was associated with neuronal degeneration in the arcuate nucleus of the hypothalamus, which lacks a blood-brain barrier (Olney 1969). He followed up this observation with a series of observations in the 1970s that administration of kainic acid, which we now know activates the GluR5-7 subtypes of glutamate receptor, and other glutamate analogues, caused not only post-synaptic cytoplasmic swelling, but also dark-cell degeneration of neurons, when viewed by electron microscopy (Olney 1971; Olney et al. 1974).

On the basis of these observations, Olney proposed the excitotoxic hypothesis, namely, that glutamate and aspartate, the principal excitatory neurotransmitters in the central nervous system, are responsible for the excitotoxic death of neurons (Olney 1985). Electron-microscopic studies in the early 1970s and 1980s described dark-cell neuronal degeneration similar to that described by Olney in experimental cerebral ischemia (McGee-Russell et al. 1970), hypoglycemia (Auer et al. 1985a, b; Kalimo et al. 1985) and status epilepticus (Griffiths et al. 1983; Ingvar et al. 1988), but the connection between these pathological states and excitotoxicity was not made.

Neurology Department, VA Greater Los Angeles Healthcare System, North Hills, CA, USA Department of Neurology and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA e-mail: [email protected]

D.G. Fujikawa (ed.), Acute Neuronal Injury: The Role of Excitotoxic Programmed Cell Death Mechanisms, DOI 10.1007/978-0-387-73226-8_1, © Springer Science+Business Media, LLC 2010

In 1983, Rothman showed that synaptic activity was necessary for hypoxic death in hippocampal neuronal cultures (Rothman 1983). Soon thereafter, it was shown that an antagonist that bound to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor reduced hypoxic-ischemic neuronal death in vivo (Simon et al. 1984). Further studies of cerebral cortical neurons in culture exposed to glutamate or NMDA showed that activation of glutamatergic receptors caused excessive Ca2+ influx through NMDA's ionotropic cationic channel (Choi 1987), and that NMDA-receptor activation results in neuronal death (Choi et al. 1987). Antagonist blockade of NMDA receptors reduced Ca2+ influx, intracellular Ca2+ concentrations, and neuronal death (Choi et al. 1988; Tymianski et al. 1993).

Subsequently, other sources for raising intracellular Ca2+ during an excitotoxic insult have been found. For example, Ca2+ can enter through the a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor subtype of glutamate channel lacking the GluR2 subunit (Pellegrini-Giampietro et al. 1992), Ca2+ is extruded from the endoplasmic reticulum (Rao et al. 2004), and the Na+-Ca2+ exchanger (NCX) at the plasma membrane is cleaved by calpains during cerebral ischemia or glutamate excitotoxicity, resulting in elevation of intracellular Ca2+ (Bano et al. 2007).

Elevated intracellular Ca2+ activates two Ca2+-dependent enzymes that in turn activate programmed cell death pathways that result in neuronal death. The first enzyme, neuronal nitric oxide synthase (nNOS), uses L-arginine as a substrate to produce nitric oxide (NO), which reacts with superoxide (O2-) to produce the toxic free radical, peroxynitrite (ONOO-) (Jourd'heuil et al. 2001). Peroxynitrite and other reactive oxygen species damage the plasma membrane, the membranes of intracellular organelles (e.g., lysosomes and mitochondria) and cause double-strand DNA cleavage of nuclear DNA (Adibhatla and Hatcher 2006; Butler and Bahr 2006; Christophe and Nicolas 2006; Wilson and McNeill 2007). Poly(ADP-ribose) polymerase-1 (PARP-1) acts to repair DNA strand breaks by generating poly(ADP-ribose) (PAR) polymers by utilizing NAD+, which in turn depletes ATP (Ha and Snyder 1999). PAR translocates to mitochondria, triggering the release of apoptosis-inducing factor (AIF), which translocates to the nucleus, acting with an unknown endonuclease to produce large-scale (50 kb) DNA cleavage (Yu et al. 2002, 2006; Andrabi et al. 2006).

The second key enzyme activated by elevated intracellular Ca2+ is the cysteine protease, calpain I. This protease cleaves structural proteins, e.g., all-spectrin (fodrin) (Sorimachi et al. 1997), causes permeabilization of lysosomal membranes (Yamashima 2004), cleaves and inactivates the NCX (Bano et al. 2007), and cleaves AIF at its amino end (Polster et al. 2005), releasing it to the cytosol, where it translocates to the nucleus.

In recent years, attention has focused almost exclusively on one of three major morphological forms of developmental cell death, apoptosis (Clarke 1990), and two programmed cell death pathways that are activated in apoptotic cell death, the intrinsic (mitochondrial) caspase pathway, and the extrinsic (death receptor) pathway (Reed 2000; Philchenkov 2004; Riedl and Shi 2004; Kumar 2007). Activation of one or both pathways has been described in the adult rodent brain subjected to cerebral ischemia (Hara et al. 1997; Chen et al. 1998; Benchoua et al. 2001; Cho et al. 2003), traumatic CNS injury (Qiu et al. 2002; Knoblach et al. 2005) and status epilepticus (SE) (Henshall et al. 2000, 2001a, b). However, the morphological evidence in the adult brain points to another of the three forms of cell death, necrosis (van Lookeren Campagne and Gill 1996; Colbourne et al. 1999; Fujikawa et al. 1999, 2000), and there is also evidence that caspase activation is age-dependent, with little caspase-3 activation in the adult brain (Hu et al. 2000; Liu et al. 2004). Also, there is evidence that the principal effector caspase, caspase-3, is not activated in vulnerable neurons in cerebral ischemia (Gill et al. 2002) and SE (Ananth et al. 2001; Fujikawa et al. 2002; Puig and Ferrer 2002; Narkilahti et al. 2003), and neither the intrinsic nor the extrinsic caspase pathway is activated in SE (Fujikawa et al. 2002; 2007; Narkilahti et al. 2003).

Whereas previously necrotic cell death was thought to be a purely passive occurrence, with cell swelling and lysis, there is accumulating evidence that it is also programmed (Kitanaka and Kuchino 1999; Leist and Jaattela 2001; Proskuryakov et al. 2003; Syntichaki and Tavernarakis 2003; Festjens et al. 2006; Golstein and Kroemer 2006), and that cell shrinkage and nuclear pyknosis with irregular, dispersed chromatin clumps, are the end result (Fujikawa et al. 1999, 2000, 2002; Fujikawa 2000). Excitotoxic neuronal necrosis, triggered by Ca2+-dependent nNOS and calpain I activation, is an example of such programmed cell death. Excitotoxic mechanisms underlie all of the major examples of acute neuronal injury - cerebral ischemia, traumatic brain injury, hypoglycemia and SE, and are the subject of this book.

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